NDUFA2

Chr 5AR

NADH:ubiquinone oxidoreductase subunit A2

Also known as: B8, CIB8, MC1DN13

NCBI Gene: 4695 ENSG00000131495 UniProt: O43678 OMIM: 602137

The encoded protein is a subunit of NADH:ubiquinone oxidoreductase (complex I) in the mitochondrial electron transport chain and regulates complex I activity and assembly through redox processes. Biallelic mutations cause mitochondrial complex I deficiency, nuclear type 13, which presents as Leigh syndrome, an early-onset progressive neurodegenerative disorder. This condition follows autosomal recessive inheritance.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex 1), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane, and may be involved in regulating complex I activity or its assembly via assistance in redox processes. Mutations in this gene are associated with Leigh syndrome, an early-onset progressive neurodegenerative disorder. Alternative splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

ARLOEUF 0.611 OMIM phenotype

Clinical Summary— NDUFA2

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.77) — some intolerance to loss-of-function variants.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 40 VUS of 103 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — NDUFA2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.61LOEUF

pLI 0.774

Z-score 2.05

OE 0.00 (0.00–0.61)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

-0.24Z-score

OE missense 1.09 (0.89–1.35)

62 obs / 56.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.61)

0≤0.351.4

Missense OE?1.09 (0.89–1.35)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 0 / 4.9Missense obs/exp: 62 / 56.9Syn Z: -0.72

ClinVar Variant Classifications

103 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS40

Likely Benign36

Benign14

Conflicting7

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	1	0	3
Likely Pathogenic	0	0	0	0	0
VUS	2	30	7	1	40
Likely Benign	0	0	24	12	36
Benign	0	0	12	2	14
Conflicting	—				7
Total	2	32	44	15	100

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

12 pathogenic / likely-pathogenic (of 18) ClinVar copy-number / structural variants overlap NDUFA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →